The present invention relates to adhesion prevention in general and to compounds, an endoscopic insufflation system and to a method for preventing adhesion formation in particular.
Adhesion formation is a major problem following surgical procedures and is a frequent cause of postoperative pain and of infertility. Adhesions are the major cause of intestinal obstruction and it is estimated that following an intra-abdominal procedure, adhesions occur in some 50 to 80 percent of patients.
The mechanism of adhesion formation can be summarized as follows: a trauma of the peritoneal lining is rapidly followed by an inflammatory reaction; exudation of plasma, and deposition of a fibrin matrix. Subsequently the lesion is healed by the degradation of the fibrin deposition, and by proliferation of the mesenchymal lining of the peritoneum. If the repair process is not completed within a few days, fibroblast proliferation starts which ultimately will end in collagen deposition and adhesion formation. Key players in this process are in particular fibrin and fibrinolysis, macrophages and their secretion products such as growth hormones and cytokines, and obviously the epithelial repair process.
From this repair process it results that. adhesion formation is largely independent from the extent of the trauma.
Prevention of adhesion formation has been attempted mechanically and by modulating the inflammatory reaction. Mechanical adhesion prevention has been attempted by barrier methods and by the instillation of viscous fluids at the end of surgery keeping the surfaces separated, or recently by coating the surfaces by biodegradable gels.
These known approaches have been only moderately successful.
It is the aim of the present invention to provide a use of a medicament, an endoscopic system, and a method for more effectively preventing adhesion.
Surprisingly, it was found that anoxemia is a major cause and/or cofactor of adhesion formation. The invention relates in particular to the use of an anoxemia preventing compound for the manufacture of a medicament for preventing adhesion formation
These local or systemic administered medicaments according to the invention reduce adhesion formation by decreasing anoxemia in particular of the peritonial lining or the consequences of peritoneal anoxemia.
Hereunder mechanisms and drugs are highlighted which are proven to be relevant to reduce/prevent adhesion formation. These drugs have hitherto not been used in adhesion prevention, at least not in the concept of prevention of ischemia and/or anoxemia and/or of the consequences of ischemia and/or anoxemia, and in particular by or during CO2 pneumoperitoneum.
The damage caused by ischemia and/or anoxemia has been investigated to occur during the period of ischemia and/or anoxemia itself, and during the reperfusion period. The mechanisms which are recognized to be involved are Ca channels, kalium efflux, free oxygen radicals, expression of a series of proteins such as VEGF (a potent angiogenic factor), other cytokines which are leucocyte attractants and heat shock proteins.
These drugs can be applied either systemically, or by local instillation during surgery, or by the prolonged administration intraperitoneally postoperatively, preferably locally e.g. by miniosmotic pumps. Experiments have shown, that this is feasible, that the local administration has the advantage that much higher concentrations of active drugs can be obtained, and that the administration for 24 to 36 hours postoperatively is sufficient.
Considering the knowledge of prevention of ischemia and/or anoxemia and/or of the consequences of ischemia and/or anoxemia the time course of administration of these drugs to prevent adhesions will obviously be different from those actually used.
Together with the hereunder explained oxygen/CO2 pneumoperitoneum or independently at least the following mechanisms and/or drugs/mechanisms can be used for the prevention of adhesions:
drugs to prevent anoxemia or the consequences thereof can also be administered, continuously or intermittently in the insufflation gas or mixture as an aerosol. For this purpose all drugs as mentioned later can be used,
activation of potassium channels;
modulation of macrophage activation and leucocyte attraction through cytokines, or their inhibitors e.g. IL8, IL6, IL1;
the effect of VEGF expression, a direct consequence of anoxemia, will be blocked by antibodies or other inhibitors;
indomethacin, which can inhibit the membrane lipid peroxidation products following anoxemia;
prostaglandin El was shown to reduce the consequences of ischemia and/or anoxemia in the liver;
allopurinol was shown to reduce the consequences of ischemia and/or anoxemia in the kuppfer cells of the liver through an effect on xanthine-oxidase;
calcium channel blockers, free radical scavengers, lipid peroxysomes, and pregnatrienes;
calcium antagonists;
prevention of hypoxia associated stress proteins;
acidosis can prevent reperfusion damage;
MP, dopamine and ATP-MgCl2 administered following the anoxemia as demonstrated for the liver.
The amount of these active ingredients of the present invention may vary depending on the formulation, but it is usually from 0.1 to 50% by weight irrespective of the manner of administration. The dose is determined taken into consideration the age, sex, and syptom of disease of the subject, the desired therapeutic effect, the period of administration, etc. However preferably a daily dose of the active ingredient is from 0.05 to 100 mg for an adult.
The invention relates also to a novel endoscopic insufflation system with supplying means for O2.
Endoscopy also called minimal access surgery has become widely used over the last years because of clearcut advantages of a decreased postoperative morbidity, less pain and a shorter hospitalization. These procedures require by means of an insufflation system or an irrigation system a distension to permit visualization.
Endoscopic surgery uses, at present, almost exclusively pure carbon dioxide gas (CO2). A standard lesion induced either by CO2 laser (superficial lesion) or by monopolar, or bipolar coagulation, (deeper lesion) cause more adhesions when the duration of the pneumoperitoneum is longer. The amount of adhesions increase with time, at least up to 2 hours. All existing insufflation systems are designed to control gas flow for pure carbon dioxide gas. Since CO2 is highly soluble in water, this gas has almost uniformly been used to induce the pneumoperitoneum, for safety reasons. In cases of accidental gas embolism the solubility in water and the exchange capacity in the lungs is estimated to be possibly of crucial life saving importance.
CO2 irritates the peritoneum, as evidenced by the pain when insufflated without anaesthesia, and by the shoulder pain following endoscopic procedures. This can be explained by the pH changes caused by CO2.
The endoscopic insufflation system according to the invention comprises gas supplying means for a insufflation line, wherein the supplying means are designed to supply gas mixtures comprising O2 and in particular gas mixtures of O2/CO2. Surprisingly it was found that O2 comprising gas mixtures reduce adhesion formation during or by pneumoperitoneum. Preferably the gas mixture is a CO2/O2 gas mixture in which gasmixture O2 is preferably present in a volume ratio from 1 to 20% and more preferably from 5 to 20% and most preferably from 5 to 10%. Parameters relevant to the upper limit of the mixing ratio are, among others, the explosiveness and the solubility of oxygen in blood.
Other O2 gas mixtures, for example with N2O or Helium can also be used as insufflation gases with preventing adhesion formation characteristics according to the invention.
For intra-abdominal endoscopy, the distension medium is generally a gas whereas for organs such as a uterus, both gases and fluids can be used.
An endoscopic insufflation system according to the invention is preferably provided with means for moistening the insufflation gas, for example by means of a sprinkler device.
Drying of peritoneal surfaces has been considered a cofactor in adhesion formation. For this reason as a single measure or together with the prevention of anoxemia using oxygen in the insufflation gas or using drugs to prevent anoxemia or the consequences thereof, it is important that the insufflated gas is moistened in order to prevent dehydration of the peritoneal surfaces Instead of moistening the insufflated gas, a sprinkler system has been devised which intermittently sprays the abdominal cavity. This sprinkler device can be attached to any canula, or preferably to the endoscope: under high pressure a small volume of irrigating fluid is intermittently and automatically sprayed in all directions of the abdominal cavity.
The insufflation system according to the invention will be further illustrated hereunder, on the basis of a number of non limitative embodiments, and with reference to the annexed drawing, wherein FIGS. 1 and 2 are extensively schematised drawings of control means of a prefered embodiment of an insufflator system according to the invention.
During endoscopy or endoscopic surgery, the abdominal cavity generally is or can intentionally be irrigated with a solution such as Ringers lactate or any other physiologic solution. The invention that anoxemia or the consequences thereof should be prevented, will use medicated irrigation fluids. For this purpose any of the substances as described can be used, in order to reduce that anoxemia or the consequences thereof, already during surgery. Alternatively, at the beginning of the surgery, the peritoneal surfaces can be coated with a biodegradable gel, which will prevent the direct contact of CO2 with the peritoneal surface and thus changes in pH and/or anoxemia.
First an overview is given of possible technical solutions to the problem of applying carbon dioxide-oxygen (CO2/O2) gas mixtures during endoscopical surgery.
The requirements of such an insufflation system according to the invention are those of a pure CO2 insufflator with additionally:
means for controlling the ratio of carbon dioxide-oxygen, which ratio is preferably controlled independently from the gas flow;
means for adjusting the ratio of carbon dioxide-oxygen during the endoscopical surgery (e.g. start the operation with pure carbon dioxide and after a while switch only temporarily to a 50% oxygen mixture);
flow control means for the carbon dioxide-oxygen gas mixture;
all materials in contact with oxygen or the gas mixture shall withstand the chemical effects of O2;
if, at least in a part of the system and temporarily, a high O2 concentration may occur, explosion protection is required.
These modifications required by the handling of O2 are known, per se, from respiration systems.
The initiation of the pneumopericoneum should preferably be done at insufflation pressures below 15 mm Hg and at a flow rate of less than 1L/min. Once the pneumoperitoneum established, the most important factor is the intra-abdominal pressure which should not exceed 30 mm of Hg. The flow rate becomes relatively unimportant.